Development of Novel Therapeutics for the Treatment of Alzheimer's Disease

开发治疗阿尔茨海默病的新疗法

• 批准号: 10121243
• 负责人: MARK T QUINN
• 金额: $ 33.75万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10121243
• 关键词: Abeta synthesis; Address; Adult; Affect; Agonist; Alaska Native; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; American Indians; Amyloid beta-42; Amyloid beta-Protein; Area; Beta Cell; Binding; Biological Markers; Cause of Death; Cell surface; Cells; Cellular biology; Communities; Dementia; Development; Disease; Dose; Epidemic; Evaluation; Event; FPR1 gene; FPR2 gene; Future; Gene Expression; High Prevalence; Human; Immune system; Immunotherapeutic agent; Individual; Inflammation; Inflammatory; Inflammatory Response; Interruption; Knowledge; Lead; Letters; Libraries; Ligands; Lipopolysaccharides; Microglia; Molecular; Monitor; Nerve Degeneration; Nuclear; Pathogenesis; Pathology; Pathway interactions; Phagocytes; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phenotype; Play; Presenile Alzheimer Dementia; Production; Reactive Oxygen Species; Research; Risk Factors; Role; Signal Transduction; Specificity; Structure-Activity Relationship; Switch Genes; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; United States; abeta oligomer; amyloid peptide; analog; animal model development; base; chemokine; cytokine; dementia risk; drug development; drug discovery; fMet-Leu-Phe receptor; formyl peptide; immunopharmacology; inhibitor/antagonist; innovation; insight; molecular modeling; monocyte; neuroinflammation; new therapeutic target; novel; novel strategies; novel therapeutics; preclinical study; prevent; prospective; receptor; response; screening; signal recognition particle receptor; small molecule; success; therapeutic target; transcriptome sequencing; uptake

Alzheimer’s disease (AD) is the most common cause of dementia and is the sixth leading cause of death in the United States. More than 5.8 million people live with AD today, and it is projected that by the year 2050, nearly 14 million people will be affected by this devastating disease. For American Indian and Alaska Native (AI/AN) communities, the effects of AD and related dementias (ADRD) will likely have an even greater impact because of the higher prevalence of risk factors associated with AD/ADRD. Indeed, the number of AI/ANs living with dementia is projected to grow over five-fold by 2060. This increase in the number of older AI/AN adults living with dementia will have a significant and detrimental impact on the vitality of whole communities. In order to address this epidemic, new therapeutics are needed that target specific pathways associated with AD/ADRD pathogenesis. For example, a significant amount of research suggests that neuroinflammation plays an active role in AD pathogenesis and that microglial cells bind to soluble amyloid β (Aβ) oligomers and Aβ fibrils via cell- surface formyl peptide receptor 2 (FPR2), resulting in an inflammatory response. Thus, we hypothesize that specific therapeutics that target and disrupt microglial cell activation pathways and inflammatory polarization could interrupt the harmful inflammatory events contributing to AD pathogenesis and favor a microglial M2 polarization that resolves inflammation. We propose to address this hypothesis by characterizing the human microglial inflammatory responses induced by soluble and aggregated Aβ, including intracellular Ca2+ flux, reactive oxygen species (ROS) production, cytokine/chemokine production, and nuclear factor κB (NF-κB) activation. We will also characterize microglial inflammatory phenotype switching (M1/M2) and gene expression (RNA-Seq) in response to Aβ activation. We will then evaluate effects of novel small molecule FPR2 antagonists on human microglial cell inflammatory responses to determine which compounds are effective inhibitors of inflammation and can enhance microglial M2 polarization. We have discovered a large number of FPR2 ligands over the years, including some specific for FPR2 and some with mixed receptor specificity for FPR1/FPR2, which can be biased towards FPR2. This library of FPR2 ligands will be useful for initial screening but will be followed by structure-activity relationship (SAR) analysis, molecular modeling, and acquisition/synthesis of new analogs. The accomplishment of these preclinical studies will lead to the development of a new class of prospective compounds that could be developed for the treatment of AD/ADRD, which could significantly benefit the AI/AN Communities. This is clearly an innovative approach to treating a prevalent disease where there are few effective drugs. The proposal will also address significant knowledge gaps relevant to the mechanisms of microglial inflammation induced by amyloid peptides. Further testing in an animal model and development of the most promising candidate FPR2 ligands will be pursued in a future proposal.

阿尔茨海默氏病（AD）是痴呆症的最常见原因，是第六个主要原因 美国。今天有超过580万人居住在广告中，预计到2050年， 近1400万人将受到这种毁灭性疾病的影响。对于美洲印第安人和阿拉斯加本地人 （AI/AN）社区，AD和相关痴呆症（ADRD）的影响可能会产生更大的影响 由于与AD/ADRD相关的风险因素的流行率更高。确实，AI/ANS生活的数量 痴呆症预计到2060年将增长超过五倍。 患有痴呆症将对整个社区的活力产生重大且有害的影响。为了 为了解决这种流行病，需要新的疗法，以针对与AD/ADRD相关的特定途径 发病。例如，大量的研究表明神经炎症起着活性 在AD发病机理中的作用，并且小胶质细胞与固体淀粉样β（Aβ）低聚物和Aβ原纤维结合通过细胞 - 表面配方肽受体2（FPR2），导致炎症反应。那我们假设 靶向和破坏小胶质细胞激活途径和炎症的特定疗法 极化可能会中断有害的有害炎症事件，导致AD发病机理和偏爱 分解注射的小胶质细胞M2极化。 我们建议通过表征人类小胶质细胞炎症反应来解决这一假设 由固体和聚集的Aβ诱导，包括细胞内Ca2+通量，活性氧（ROS） 产生，细胞因子/趋化因子产生和核因子κB（NF-κB）激活。我们还将描述 小胶质细胞炎症表型转换（M1/M2）和基因表达（RNA-SEQ）响应Aβ 激活。然后，我们将评估新型小分子FPR2拮抗剂对人小胶质细胞的影响 炎症反应以确定哪些化合物是有效的感染抑制剂，并且可以增强 小胶质细胞M2极化。多年来，我们发现了大量的FPR2配体，包括一些 针对FPR2的特异性，有些具有FPR1/FPR2的混合受体特异性，这可能会偏向FPR2。 该FPR2配体库将有助于初始筛选，但随后将是结构活动关系 （SAR）分析，分子建模和新类似物的采集/合成。 这些临床前研究的成就将导致发展新类 可以开发用于治疗AD/ADRD的潜在化合物，可以 显着使AI/A社区受益。这显然是一种治疗普遍的创新方法 有效药物很少的疾病。该提案还将解决相关的重要知识差距 淀粉样蛋白酶诱导的小胶质细胞注射机理。在动物模型中进行进一步测试 并将在未来的提案中追求最有望的候选FPR2配体的发展。

项目成果

Novel c-Jun N-Terminal Kinase (JNK) Inhibitors with an 11H-Indeno[1,2-b]quinoxalin-11-one Scaffold.

• DOI: 10.3390/molecules26185688
• 发表时间: 2021-09-20
• 期刊: Molecules (Basel, Switzerland)
• 作者: Liakhov SA;Schepetkin IA;Karpenko OS;Duma HI;Haidarzhy NM;Kirpotina LN;Kovrizhina AR;Khlebnikov AI;Bagryanskaya IY;Quinn MT
• 通讯作者: Quinn MT

Chemical Composition and Immunomodulatory Activity of Essential Oils from Rhododendron albiflorum.

• DOI: 10.3390/molecules26123652
• 发表时间: 2021-06-15
• 期刊: Molecules (Basel, Switzerland)
• 作者: Schepetkin IA;Özek G;Özek T;Kirpotina LN;Khlebnikov AI;Quinn MT
• 通讯作者: Quinn MT

Changes in vitality in response to acute stress: an investigation of the role of anxiety and physiological reactivity.

• DOI: 10.1080/10615806.2021.1929935
• 发表时间: 2022-03
• 期刊: Anxiety, stress, and coping
• 作者: Tintzman CS;Kampf TD;John-Henderson NA
• 通讯作者: John-Henderson NA

Elder-led cultural identity program as counterspace at a public university: Narratives on sense of community, empowering settings, and empowerment.

老年人主导的文化认同计划作为公立大学的反空间：关于社区意识、赋权环境和赋权的叙述。

• DOI: 10.1002/ajcp.12673
• 发表时间: 2023
• 期刊: American journal of community psychology
• 影响因子: 3.1
• 作者: Buckingham,SaraL;Schroeder,TieraUqiilaq;Hutchinson,JacyR
• 通讯作者: Hutchinson,JacyR

Investigation of the 2018 thick-billed murre (Uria lomvia) die-off on St. Lawrence Island rules out food shortage as the cause.

对 2018 年圣劳伦斯岛厚嘴海鸦 (Uria lomvia) 死亡事件的调查排除了食物短缺的原因。

• DOI: 10.1016/j.dsr2.2020.104879
• 发表时间: 2020
• 期刊: Deep-sea research. Part II, Topical studies in oceanography
• 作者: Will,Alexis;Thiebot,Jean-Baptiste;Ip,HonS;Shoogukwruk,Punguk;Annogiyuk,Morgan;Takahashi,Akinori;Shearn-Bochsler,Valerie;Killian,MaryLea;Torchetti,Mia;Kitaysky,Alexander
• 通讯作者: Kitaysky,Alexander